TY - JOUR
T1 - CXCL1-CXCR1/2 signaling is induced in human temporal lobe epilepsy and contributes to seizures in a murine model of acquired epilepsy
AU - di Sapia, Rossella
AU - Zimmer, Till S.
AU - Kebede, Valentina
AU - Balosso, Silvia
AU - Ravizza, Teresa
AU - Sorrentino, Diletta
AU - Castillo, Manuel Alejandro Montano
AU - Porcu, Luca
AU - Cattani, Franca
AU - Ruocco, Anna
AU - Aronica, Eleonora
AU - Allegretti, Marcello
AU - Brandolini, Laura
AU - Vezzani, Annamaria
N1 - Funding Information: The authors thank the contribution of Dr. V. Iori and Dr C. Kostoula in the initial phases of this study. This preclinical study was supported by an unrestricted grant to A.V. from Dompe’ Farmaceutici S.p.a. Human tissue study was supported by a grant to E.A. from the European Union 's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no. 722053 (EU-GliaPhD; TSZ, EA) and no. 952455 (EpiEpiNet; AE), Funding Information: The authors thank the contribution of Dr. V. Iori and Dr C. Kostoula in the initial phases of this study. This preclinical study was supported by an unrestricted grant to A.V. from Dompe? Farmaceutici S.p.a. Human tissue study was supported by a grant to E.A. from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no. 722053 (EU-GliaPhD; TSZ, EA) and no. 952455 (EpiEpiNet; AE) Publisher Copyright: © 2021
PY - 2021/10/1
Y1 - 2021/10/1
N2 - CXCL1, a functional murine orthologue of the human chemokine CXCL8 (IL-8), and its CXCR1 and CXCR2 receptors were investigated in a murine model of acquired epilepsy developing following status epilepticus (SE) induced by intra-amygdala kainate. CXCL8 and its receptors were also studied in human temporal lobe epilepsy (TLE). The functional involvement of the chemokine in seizure generation and neuronal cell loss was assessed in mice using reparixin (formerly referred to as repertaxin), a non-competitive allosteric inhibitor of CXCR1/2 receptors. We found a significant increase in hippocampal CXCL1 level within 24 h of SE onset that lasted for at least 1 week. No changes were measured in blood. In analogy with human TLE, immunohistochemistry in epileptic mice showed that CXCL1 and its two receptors were increased in hippocampal neuronal cells. Additional expression of these molecules was found in glia in human TLE. Mice were treated with reparixin or vehicle during SE and for additional 6 days thereafter, using subcutaneous osmotic minipumps. Drug-treated mice showed a faster SE decay, a reduced incidence of acute symptomatic seizures during 48 h post-SE, and a delayed time to spontaneous seizures onset compared to vehicle controls. Upon reparixin discontinuation, mice developed spontaneous seizures similar to vehicle mice, as shown by EEG monitoring at 14 days and 2.5 months post-SE. In the same epileptic mice, reparixin reduced neuronal cell loss in the hippocampus vs vehicle-injected mice, as assessed by Nissl staining at completion of EEG monitoring. Reparixin administration for 2 weeks in mice with established chronic seizures, reduced by 2-fold on average seizure number vs pre-treatment baseline, and this effect was reversible upon drug discontinuation. No significant changes in seizure number were measured in vehicle-injected epileptic mice that were EEG monitored in parallel. Data show that CXCL1-IL-8 signaling is activated in experimental and human epilepsy and contributes to acute and chronic seizures in mice, therefore representing a potential new target to attain anti-ictogenic effects.
AB - CXCL1, a functional murine orthologue of the human chemokine CXCL8 (IL-8), and its CXCR1 and CXCR2 receptors were investigated in a murine model of acquired epilepsy developing following status epilepticus (SE) induced by intra-amygdala kainate. CXCL8 and its receptors were also studied in human temporal lobe epilepsy (TLE). The functional involvement of the chemokine in seizure generation and neuronal cell loss was assessed in mice using reparixin (formerly referred to as repertaxin), a non-competitive allosteric inhibitor of CXCR1/2 receptors. We found a significant increase in hippocampal CXCL1 level within 24 h of SE onset that lasted for at least 1 week. No changes were measured in blood. In analogy with human TLE, immunohistochemistry in epileptic mice showed that CXCL1 and its two receptors were increased in hippocampal neuronal cells. Additional expression of these molecules was found in glia in human TLE. Mice were treated with reparixin or vehicle during SE and for additional 6 days thereafter, using subcutaneous osmotic minipumps. Drug-treated mice showed a faster SE decay, a reduced incidence of acute symptomatic seizures during 48 h post-SE, and a delayed time to spontaneous seizures onset compared to vehicle controls. Upon reparixin discontinuation, mice developed spontaneous seizures similar to vehicle mice, as shown by EEG monitoring at 14 days and 2.5 months post-SE. In the same epileptic mice, reparixin reduced neuronal cell loss in the hippocampus vs vehicle-injected mice, as assessed by Nissl staining at completion of EEG monitoring. Reparixin administration for 2 weeks in mice with established chronic seizures, reduced by 2-fold on average seizure number vs pre-treatment baseline, and this effect was reversible upon drug discontinuation. No significant changes in seizure number were measured in vehicle-injected epileptic mice that were EEG monitored in parallel. Data show that CXCL1-IL-8 signaling is activated in experimental and human epilepsy and contributes to acute and chronic seizures in mice, therefore representing a potential new target to attain anti-ictogenic effects.
KW - Chemokine
KW - Glia
KW - Neurodegeneration
KW - Neuroinflammation
KW - Reparixin
KW - Status epilepticus
UR - http://www.scopus.com/inward/record.url?scp=85112671583&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.nbd.2021.105468
DO - https://doi.org/10.1016/j.nbd.2021.105468
M3 - Article
C2 - 34358616
SN - 0969-9961
VL - 158
JO - Neurobiology of Disease
JF - Neurobiology of Disease
M1 - 105468
ER -